Herman T S, Teicher B A, Coleman C N
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Cancer Res. 1990 Aug 15;50(16):5055-9.
The effects of SR-4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cell cytotoxic agent, were assayed against the FSaIIC murine fibrosarcoma in vitro and in vivo alone and in conjunction with hyperthermia and radiation. In vitro, a concentration of 500 microM of SR-4233 upon exposure of the cells for 1 h decreased the survival of hypoxic cells by about 1 log more than euoxic cells at 37 degrees C and pH 7.40. At the same concentration at pH 6.45, this difference in cytotoxicity increased to about 3 logs. In conjunction with 42 or 43 degrees C hyperthermia at pH 7.40, the killing of both euoxic and hypoxic cells was markedly increased (hypoxic greater than oxic), and the effect of hyperthermia on SR-4233 cytotoxicity was further increased at pH 6.45. SR-4233 proved to be an effective radiosensitizer of hypoxic cells in vitro, producing an enhancement ratio of 2.6 +/- 0.2 at pH 7.40 and 2.7 +/- 0.2 at pH 6.45. In vivo, however, SR-4233 (50 mg/kg) used with single dose radiation (10, 20, or 30 Gy) did not alter the slope of the radiation dose-dependent tumor growth delay curve but did produce a significant additive increase in tumor growth delay. Local hyperthermia (43 degrees C, 30 min) plus SR-4233 (30 mg/kg) produced a tumor growth delay of 9.1 +/- 2.2 days, whereas SR-4233 alone caused a tumor growth delay of only 1.7 +/- 0.9 days and the hyperthermia, only 1.4 +/- 0.7 days. The tumor growth delay increased to 28.2 +/- 4.4 days with the addition of daily radiation (3 Gy for 5 days) to SR-4233 and hyperthermia given on treatment day 1 only. Hoechst 33342 dye-selected tumor subpopulation analysis at 24 h following treatment demonstrated that SR-4233 (30 mg/kg) was more toxic to dim (presumably hypoxic) cells by about 1.8-fold. The addition of hyperthermia to treatment with SR-4233 increased the killing of dim cells by about 5-fold but of bright cells by only 2-fold. Trimodality treatment with SR-4233, hyperthermia, and radiation increased the killing of bright cells by about 6.5-fold and of dim cells by about 16.5-fold as compared with radiation alone. These results indicate that SR-4233 might be used quite effectively with radiation and/or hyperthermia to treat tumors with significant hypoxic subpopulations.
缺氧细胞细胞毒性药物SR-4233（3-氨基-1,2,4-苯并三嗪-1,4-二氧化物）的作用，在体外和体内单独以及与热疗和放疗联合应用时，对FSaIIC小鼠纤维肉瘤进行了测定。在体外，在37℃和pH 7.40条件下，500 microM的SR-4233浓度作用细胞1小时，与常氧细胞相比，缺氧细胞的存活率降低约1个对数。在pH 6.45的相同浓度下，这种细胞毒性差异增加到约3个对数。在pH 7.40条件下，与42或43℃热疗联合应用时，常氧和缺氧细胞的杀伤均显著增加（缺氧细胞大于常氧细胞），在pH 6.45时，热疗对SR-4233细胞毒性的影响进一步增加。SR-4233在体外被证明是缺氧细胞的有效放射增敏剂，在pH 7.40时增强比为2.6±0.2，在pH 6.45时为2.7±0.2。然而，在体内，单剂量放疗（10、20或30 Gy）联合使用SR-4233（50 mg/kg）并没有改变放射剂量依赖性肿瘤生长延迟曲线的斜率，但确实使肿瘤生长延迟有显著的相加性增加。局部热疗（43℃，30分钟）加SR-4233（30 mg/kg）使肿瘤生长延迟9.1±2.2天，而单独使用SR-4233仅使肿瘤生长延迟1.7±0.9天，热疗仅使肿瘤生长延迟1.4±0.7天。仅在治疗第1天给予SR-4233和热疗并联合每日放疗（3 Gy，共5天），肿瘤生长延迟增加到28.2±4.4天。治疗后24小时进行的Hoechst 33342染料选择肿瘤亚群分析表明，SR-4233（30 mg/kg）对暗（推测为缺氧）细胞的毒性约高1.8倍。在SR-4233治疗中加入热疗使暗细胞的杀伤增加约5倍，但亮细胞仅增加2倍。与单独放疗相比，SR-4233、热疗和放疗三联治疗使亮细胞的杀伤增加约6.5倍，暗细胞增加约16.5倍。这些结果表明，SR-4233与放疗和/或热疗联合使用可能非常有效地治疗具有显著缺氧亚群的肿瘤。
